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Nat Chem Biol. 2013 Jan;9(1):51-8. doi: 10.1038/nchembio.1134. Epub 2012 Nov 25.

Conformational stabilization of ubiquitin yields potent and selective inhibitors of USP7.

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1
Department of Early Discovery Biochemistry, Genentech Inc., San Francisco, California, USA.

Erratum in

  • Nat Chem Biol. 2013 Mar;9(3):192.

Abstract

Protein conformation and function are often inextricably linked, such that the states a protein adopts define its enzymatic activity or its affinity for various partners. Here we combine computational design with macromolecular display to isolate functional conformations of ubiquitin that tightly bind the catalytic core of the oncogenic ubiquitin-specific protease 7 (USP7) deubiquitinase. Structural and biochemical characterization of these ubiquitin variants suggest that remodeled backbone conformations and core packing poise these molecules for stronger interactions, leading to potent and specific inhibition of enzymatic activity. A ubiquitin variant expressed in human tumor cell lines binds and inhibits endogenous USP7, thereby enhancing Mdm2 proteasomal turnover and stabilizing p53. In sum, we have developed an approach to rationally target macromolecular libraries toward the remodeling of protein conformation, shown that engineering of ubiquitin conformation can greatly increase its interaction with deubiquitinases and developed powerful tools to probe the cellular role of USP7.

Comment in

PMID:
23178935
DOI:
10.1038/nchembio.1134
[Indexed for MEDLINE]

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